Endophenotype Of Schizophrenia Research Articles

EL11-2 The better practices for neurophysiological endophenotypes of schizophrenia

EL11-2 The better practices for neurophysiological endophenotypes of schizophrenia

Neurophysiological Biomarkers in Schizophrenia—P50, Mismatch Negativity, and TMS-EMG and TMS-EEG

Impaired early auditory processing is a well characterized finding in schizophrenia that is theorized to contribute to clinical symptoms, cognitive impairment, and social dysfunction in patients. Two neurophysiological measures of early auditory processing, P50 gating (“P50”) and mismatch negativity (MMN), which measure sensory gating and detection of change in auditory stimuli, respectively, are consistently shown to be impaired in patients with schizophrenia. Transcranial magnetic stimulation (TMS) may also be a potential method by which sensory processing can be assessed, since TMS paradigms can be used to measure GABAB-mediated cortical inhibition that is linked with sensory gating. In this review, we examine the potential of P50, MMN and two TMS paradigms, cortical silent period (CSP) and long-interval intracortical inhibition (LICI), as endophenotypes as well as their ability to be used as predictive markers for interventions targeted at cognitive and psychosocial functioning. Studies consistently support a link between MMN, P50, and cognitive dysfunction, with robust evidence for a link between MMN and psychosocial functioning in schizophrenia as well. Importantly, studies have demonstrated that MMN can be used to predict performance in social and cognitive training tasks. A growing body of studies also supports the potential of MMN to be used as an endophenotype, and future studies are needed to determine if MMN can be used as an endophenotype specifically in schizophrenia. P50, however, has weaker evidence supporting its use as an endophenotype. While CSP and LICI are not as extensively investigated, growing evidence is supporting their potential to be used as an endophenotype in schizophrenia. Future studies that assess the ability of P50, MMN, and TMS neurophysiological measures to predict performance in cognitive and social training programs may identify markers that inform clinical decisions in the treatment of neurocognitive impairments in schizophrenia.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

A common variant of the NOTCH4 gene modulates functional connectivity of the occipital cortex and its relationship with schizotypal traits

BackgroundSchizotypal traits are considered as inheritable traits and the endophenotype for schizophrenia. A common variant in the NOTCH4 gene, rs204993, has been linked with schizophrenia, but the neural underpinnings are largely unknown.MethodsIn present study, we compared the differences of brain functions between different genotypes of rs204993 and its relationship with schizotypal traits among 402 Chinese Han healthy volunteers. The brain function was evaluated with functional connectivity strength (FCS) using the resting-state functional magnetic resonance image(rs-fMRI). The schizotypal traits were measured by the schizotypal personality questionnaire (SPQ).ResultsOur results showed that carriers with the AA genotype showed reduced FCS in the left occipital cortex when compared with carriers with the AG and GG genotypes, and the carriers with the AG genotype showed reduced FCS in the left occipital cortex when compared with carriers with the GG genotype. The FCS values in the left occipital lobe were negatively associated with the SPQ scores and its subscale scores within the carriers with the GG genotype, but not within the carriers with AA or AG genotype.ConclusionOur results suggested that the common variant in the NOTCH4 gene, rs204993, modulates the function of the occipital cortex, which may contribute to schizotypal traits. These findings provide insight for genetic effects on schizotypal traits and its potential neural substrate.

Effect of gabapentin on sleep-deprivation-induced disruption of prepulse inhibition.

There are controversial reports on the effects of gabapentin in respect to psychotic symptoms. Prepulse inhibition of the acoustic startle response is an operational measure of sensorimotor gating. In laboratory rodents, deficits in sensorimotor gating are used to model behavioral endophenotypes of schizophrenia. Sleep deprivation disrupts prepulse inhibition and can be used as a psychosis model to evaluate effects of gabapentin. This study aimed to investigate behavioral effects of gabapentin in both naïve and sleep-deprived rats. Sleep deprivation was induced in male Wistar rats by using the modified multiple platform technique in a water tank for 72h. The effect of water tank itself was studied in a sham group. The effects of oral acute and subchronic (4.5days) gabapentin doses (25, 100, or 200mg/kg/day) on sensorimotor gating and locomotor activity was evaluated by prepulse inhibition test and locomotor activity test, respectively. Plasma gabapentin levels of some groups and body weights of all groups were also assessed. Sleep deprivation disrupted prepulse inhibition, increased locomotor activity, reduced gabapentin plasma levels, and body weights. Some gabapentin doses disrupted sensorimotor gating irrespective of sleep condition. Some gabapentin doses increased locomotor activity in non-sleep-deprived rats and decreased locomotor activity in sleep-deprived rats. On the contrary, gabapentin did not normalize sleep deprivation-induced disruption in sensorimotor gating. Sleep deprivation via modified multiple platform technique could be used as an animal model for psychosis. Gabapentin may have dose- and duration-dependent effects on sensorimotor gating and locomotor activity.

The Effect of Chronic Methamphetamine Treatment on Schizophrenia Endophenotypes in Heterozygous Reelin Mice: Implications for Schizophrenia.

Reelin has been implicated in the development of schizophrenia but the mechanisms involved in this interaction remain unclear. Chronic methamphetamine (Meth) use may cause dopaminergic sensitisation and psychosis and has been proposed to affect brain dopamine systems similarly to changes seen in schizophrenia. We compared the long-term effect of chronic Meth treatment between heterozygous reelin mice (HRM) and wildtype controls (WT) with the aim of better understanding the role of reelin in schizophrenia. Meth pretreatment induced sensitisation to the effect of an acute Meth challenge on locomotor activity, but it had no effect on baseline PPI or sociability and social preference. In all behavioural models, HRM did not significantly differ from WT at baseline, except spontaneous exploratory locomotor activity which was higher in HRM than WT, and sociability which was enhanced in HRM. Locomotor hyperactivity sensitisation was not significantly different between HRM and WT. Chronic Meth treatment reduced spontaneous locomotor activity to the level of WT. No deficits in PPI or social behaviour were induced by chronic Meth pretreatment in either strain. In conclusion, these data do not support a role of reelin in schizophrenia, at least not in HRM and in the methamphetamine sensitisation model.

EEG microstates are a candidate endophenotype for schizophrenia

Electroencephalogram microstates are recurrent scalp potential configurations that remain stable for around 90 ms. The dynamics of two of the four canonical classes of microstates, commonly labeled as C and D, have been suggested as a potential endophenotype for schizophrenia. For endophenotypes, unaffected relatives of patients must show abnormalities compared to controls. Here, we examined microstate dynamics in resting-state recordings of unaffected siblings of patients with schizophrenia, patients with schizophrenia, healthy controls, and patients with first episodes of psychosis (FEP). Patients with schizophrenia and their siblings showed increased presence of microstate class C and decreased presence of microstate class D compared to controls. No difference was found between FEP and chronic patients. Our findings suggest that the dynamics of microstate classes C and D are a candidate endophenotype for schizophrenia.

Temperament and Character Profile and Its Clinical Correlates in Male Patients with Dual Schizophrenia.

Personality traits are relevant in understanding substance use disorders (SUD) and schizophrenia (SZ), but few works have also included patients with dual schizophrenia (SZ+) and personality traits. We explored personality profile in a sample of 165 male patients under treatment, using the Temperament and Character Inventory-Revised. The participants were assigned to three groups of 55 patients each, according to previous diagnosis: SUD, SZ- and SZ+ (without/with SUD). We analyzed their clinical characteristics, relating them to personality dimensions. The SUD and SZ+ groups scored higher than SZ- in Novelty/Sensation Seeking. SZ- and SZ+ presented higher Harm Avoidance and lower Persistence than the SUD group. SZ+ patients showed the lowest levels of Self-directedness, while SZ- and SZ+ had higher scores in Self-transcendence than the SUD group. Several clinical characteristics were associated with personality dimensions depending on diagnosis, and remarkably so for psychiatric symptoms in the SZ- and SZ+ groups. The three groups had a maladaptive personality profile compared to general population. Our results point to different profiles for SUD versus SZ, while both profiles appear combined in the SZ+ group, with extreme scores in some traits. Thus, considering personality endophenotypes in SZ+ could help in designing individualized interventions for this group.

Neurocognitive and neurophysiological endophenotypes in schizophrenia: An overview.

Schizophrenia (SCZ) is a severe psychotic disorder that affects up to 1% of the US population and it is associated with progressive impairment in social functioning and cognition. Nonetheless, despite its high burden, the pathophysiology of SCZ, including the genetic and biological mechanisms underlying the development and manifestation of the disorder, remains largely elusive. Endophenotypes are subtypes of biological markers that are more closely related to the genetic vulnerability for a disorder (e.g., SCZ). Recently, research on endophenotypes has identified several parameters that may prove useful in shedding light over the underlying neurobiology of SCZ. In this article, we provide an overview of the most established SCZ endophenotypes in the domains of neurocognition (attention deficits, working and verbal declarative memory dysfunctions) and neurophysiology (pre-pulse inhibition, anti-saccade impairment, event-related potential deficits) along with some novel, sleep-based measures (reduced sleep spindles and sleep slow waves). We also discuss recent conceptual advances in the field that may lead to novel, personalized treatment interventions for patients affected by this devastating mental illness.

S138. A PRELIMINARY STUDY ON ILLNESS INSIGHT MEASURED BY THE RELATIONSHIP BETWEEN ERN PATTERNS AND MMPI RESULTS IN PATIENTS WITH SCHIZOPHRENIA

BackgroundThe error-related negativity (ERN) is an event-related brain potential waveform peaking about 50 ms after error commission in choice-response tasks and may indicate a conflict between neural representations of correct and incorrect responses as stimulus processing continues after an error. Most previous studies consistently reported a reduced event-related potential (ERP) amplitude in patients with schizophrenia compared with normal controls. Some self-report measures derived from the Minnesota Multiphasic Personality Inventory (MMPI) are known to be associated with clinical observations in carefully diagnosed schizophrenia patients. In the MMPI, an elevation of the validity scales in the MMPI best distinguishes patients with schizophrenia from patients feigning schizophrenia, and the MMPI validity scales are known to provide a good reflection of illness insight in schizophrenia.Both the amplitudes of the Pe of the ERN and the scores of the MMPI validity scales are supposed to reflect, directly or indirectly, the illness insight of patients with schizophrenia.When the abovementioned results obtained in studies on the ERN or MMPI in patients with schizophrenia are taken together, we may presume that a certain relationship exists between the results of the ERN and the MMPI validity scales in terms of illness insight.Interestingly, as far as we know, there are no published studies that looked at the results of the ERN and the MMPI at the same time.We tried to perform an integrative examination of the relationship between the results of the ERN and MMPI tests in patients with schizophrenia as a method of measuring illness insight in patients with schizophrenia.MethodsWe reviewed the medical records of who were diagnosed as having schizophrenia based on the DSM-5.The protocol for the general ERP and ERN are as follows.64 channels with M1 and M2 as reference electrodesImpedance: < 1 kΩERN: 1000 msERPs were recorded while the patients were performing the Stroop test. Independently of the ERP recording, the patients received an MMPI test.The relationship between the latency and amplitude of the ERN and the demographic and clinical variables was analyzed by a t-test, and correlation analyses were used for categorical and continuous variables. The statistical significance was set at p < 0.05.ResultsOf the total 18 patients (8 men and 10 women; age = 41.6 ± 15.8) whose data were reviewed, 5 were excluded due to poor understanding of the ERN instructions.Table 1. Demographic and clinical information of participated patientswith schizophreniaTable 2. Partial correlation coefficients on variables after controlling for age and gender.DiscussionThe results for the association of ERN amplitude and latency with the MMPI validity scales showed that latency measures were positively associated with the MMPI validity scales that were related to the assessment of the overestimation of responses. Individuals who tended to exaggerate problems through over-responses showed increased ERN amplitude but decreased ERN Pe amplitude. Although caution is needed to interpret the results of this study due to limitations, our results suggest that ERP measurement could act as a biological marker for endophenotype in schizophrenia. Furthermore, ERP measurement might be used to visualize or to make concrete illness insight, which by its nature is difficult to measure objectively.ReferencesYeung N, Botvinick MM, Cohen JD. The neural basis of error detection: conflict monitoring and the error-related negativity. Psychol Rev. 2004 Oct;111(4):931–959.Kansal V, Patriciu I, Kiang M. Illness insight and neurophysiological error-processing deficits in schizophrenia. Schizophr Res. 2014 Jun;156(1):122–7.

T184. THE ROLE OF ADVERSE CHILDHOOD EXPERIENCES IN THE DEVELOPMENT OF A MORE SEVERE TYPE OF SCHIZOPHRENIA

BackgroundThe prevalence of Adverse Childhood Experiences (ACEs) in psychotic patients ranges from 45 to 91%. Some authors argue that the risk of developing psychosis is higher in subjects who were exposed to multiple types of ACEs and that trauma multiplicity has a negative clinical impact in psychosis, while others argue that specific types of trauma are related to specific features of disease, taking away importance at the dose-response hypothesis.Most of the studies about ACEs and schizophrenia have been conducted in North America or Western Europe and there is a lack of information on this topic in developing regions, excluding the possibility of finding regional differences in ACEs frequency and its consequences. The present research provides information about the prevalence of ACEs in schizophrenic patients and in a control sample, and explores the clinical impact of trauma multiplicity in a schizophrenic adult population of Argentina.MethodsAn observational, multicentric and cross-sectional study was conducted at three different hospitals located in Buenos Aires. One hundred patients with schizophrenia and 50 subjects without a mental disease were recruited. Information about adverse childhood experiences was obtained from the Spanish version of the Adverse Childhood Experiences questionnaire (ACE-Q). Clinical severity of schizophrenia was measured with the Positive and Negative Syndrome Scale (PANSS) and with the hallucination subscale of the Psychotic Symptom Rating Scale (PSYRATS), suicidal behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), treatment adherence with the Drug Attitude Inventory (DAI-10), global functioning with the Global Assessment Functioning Scale (GAF), theory of mind with the Hinting Task test and emotional processing with the Reading the mind in the eyes test.To analyze the impact of trauma multiplicity on clinical variables of schizophrenia, the patient sample was divided into 2 groups according to the number of ACEs suffered. As a cut-off point, a statistical criterion corresponding to the median number of ACEs was chosen and the sample was divided between those who suffered 0–4 ACEs and those with 5 or more ACEs. Statistical analysis was carried out using SAS software.ResultsThe prevalence of at least one ACE in schizophrenic patients was almost double in comparison with the control group (92% vs 54%). Patients with trauma multiplicity showed a PANSS-N score lower than the group with lower number of ACEs (0–4 ACEs= 24.51 ± 5.17 vs. ≥ 5 ACEs= 21.04 ± 4.22; p= <0.001). PSYRATS score was higher in patients with 5 or more ACEs (0–4 ACEs= 6 points, Q1-Q3: 3–18 vs. ≥ 5 ACEs= 12 points, Q1-Q3: 5–23; p= 0.042). Patients with 5 or more ACEs scored higher in death ideation (0–4 ACEs= 22 (40.00%) vs. ≥ 5 ACEs= 28 (62.22%); p= 0.027). The prevalence of suicidal attempts was also higher (0–4 ACEs= 22 (40.00%) vs. ≥ 5 ACEs= 27 (60.00%); p= 0.047), as well as the median number of suicide attempts (0–4 ACEs= 0 (0–1) vs. ≥ 5 ACEs= 1 (0–2); p= 0.039). Also, women with 5 or more ACEs showed higher suicidal ideation score (0–4 ACEs= 0 (0–1) vs. ≥ 5 ACEs= 2 (0–4); p= 0.035). No other clinical variables under study showed differences between the groups.DiscussionTrauma multiplicity is associated with less negative symptoms, greater suicidal behavior and auditory hallucinations resistant to antipsychotic therapy. Further studies should be done to determine if this might be a specific endophenotype of schizophrenia. The high prevalence of ACEs in our study could be explained by the questionnaire applied, as it includes a large number of ACEs in comparison with others and it could also be linked to regional and cultural characteristics, as there is little information about ACEs prevalence of in South America.

S177. IMPACT OF NOS1AP AND ITS INTERACTION PARTNERS AT THE GLUTAMATERGIC SYNAPSE ON WORKING MEMORY NETWORKS - AN FMRI IMAGING GENETICS STUDY

BackgroundN-methyl-D-aspartate receptor (NMDAR) hypofunction is an important pathophysiological mechanism in schizophrenia. At the postsynapse the NMDAR interacts with the post-synaptic density (PSD). Neuronal nitric oxide synthase 1 (NOS1) binds to the PSD scaffolding proteins PSD-93 and PSD-95, enabling NMDAR-mediated release of nitric oxide via NOS1. NOS1AP (adaptor of NOS1) is capable of disrupting the interactions between NOS1, PSD-93, and PSD95. Therefore, NOS1AP is closely involved in both glutamatergic and nitrinergic neurotransmission. NOS1AP has been implicated as a risk gene for schizophrenia and cognitive dysfunction. Its increased expression has been observed in dorsolateral prefrontal post-mortem brain tissue of patients with schizophrenia, and NOS1AP SNPs have been associated with established schizophrenia endophenotypes. These findings suggest that the influence of NOS1AP variants should be observable in neural systems implicated in schizophrenia. In the present study, we investigate the impact of NOS1AP and its interaction partners at the glutamatergic synapse on the cortical working memory (WM) networks using fMRI and a gene set analysis approach.Methods97 right-handed individuals with no personal or family history of psychiatric disorders underwent fMRI in a 3T Siemens Trio scanner during the performance of a visuospatial change detection WM task. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimize macro-anatomical variability between subjects. Subsequently, data were analyzed using a random-effects multi-subject general linear model. We investigated 19 regions of interest (ROIs) within the core fronto-parietal WM network. We studied all phases of our WM paradigm (encoding, maintenance, retrieval), which were modeled by a total of 5 regressors (encoding, delays 1–3, retrieval). Genetic data was quality controlled and imputed using the RICOPILI pipeline. Gene-set analyses of the 19 ROIs were performed using MAGMA. Two gene sets were selected: 1) NOS1AP/NOS1; 2) NOS1AP/glutamatergic synapse. We applied a Bonferroni correction for the total of 19 ROIs and 5 regressors (95 tests) to both analyses.ResultsBoth gene set analyses revealed multiple associations between brain activation in core fronto-parietal WM areas. For the NOS1/NOS1AP set, most associations were observed during the late maintenance phase (Delay 3) of our WM paradigm. One association was significant Bonferroni correction: a cluster in the left intraparietal sulcus during the late maintenance phase (Delay 3; β=2.2459, SD=0.0239, SE=0.6451, p=0,00025). For NOS1AP / glutamatergic synapse interaction partners, two associations were significant after Bonferroni correction: a cluster in the right IPS during the early maintenance phase (Delay 1; β=0.8525, SD=0.0257, SE=0.2127, p=0.0000308) and a cluster in a different part of the right IPS during the late maintenance phase (Delay 3; β=0.7186, SD=0.0216, SE=0.2119, p=0,000348).DiscussionIn our gene set analyses we observed multiple associations between brain activation during WM and NOS1AP and its interaction partners, which were most pronounced during the late maintenance phase of our WM task in bilateral areas within the IPS. Both the more constrained NOS1AP / NOS1 gene set and the NOS1AP / glutamatergic synapse gene set showed similar association patterns. Our results implicate the NOS1AP interactome and the glutamatergic system in information processing and brain function in a cognitive domain strongly impaired in schizophrenia. They also indicate that altered activation of parietal WM areas during the maintenance phase is most strongly affected.

Psychomotor Slowing in Schizophrenia: Implications for Endophenotype and Biomarker Development.

Motor abnormalities (e.g., dyskinesia, psychomotor slowing, neurological soft signs) are core features of schizophrenia that occur independent of drug treatment and are associated with the genetic vulnerability and pathophysiology for the illness. Among this list, psychomotor slowing in particular is one of the most consistently observed and robust findings in the field. Critically, psychomotor slowing may serve as a uniquely promising endophenotype and/or biomarker for schizophrenia considering it is frequently observed in those with genetic vulnerability for the illness, predicts transition in subjects at high-risk for the disorder, and is associated with symptoms and recovery in patients. The purpose of the present review is to provide an overview of the history of psychomotor slowing in psychosis, discuss its possible neural underpinnings, and review the current literature supporting slowing as a putative endophenotype and/or biomarker for the illness. This review summarizes substantial evidence from a diverse array of methodologies and research designs that supports the notion that psychomotor slowing not only reflects genetic vulnerability, but is also sensitive to disease processes and the pathophysiology of the illness. Furthermore, there are unique deficits across the cognitive (prefix "psycho") and motor execution (root word "motor") aspects of slowing, with cognitive processes such as planning and response selection being particularly affected. These findings suggest that psychomotor slowing may serve as a promising endophenotype and biomarker for schizophrenia that may prove useful for identifying individuals at greatest risk and tracking the course of the illness and recovery.

Genetic Deciphering of Prepulse Inhibition Reveals the Putative Role of an Atypical Cadherin in Schizophrenia Pathogenesis

Prepulse inhibition (PPI) of the startle response reflects a sensory-motor gating mechanism, and impaired PPI is a characteristic endophenotype of schizophrenia. We have previously localized quantitative trait loci (QTL) for PPI in chromosome 10 by analyzing 1,010 F2 mice derived by crossing C57BL/6N (B6) animals that showed high PPI with C3H/HeN (C3) animals that showed low PPI. However, large number of genes in the QTL hinders delineating precise role of genes in defining PPI.

Función ejecutiva, lenguaje pragmático y perfiles psicopatológicos según la CBCL en niños con trastornos del neurodesarrollo y antecedentes familiares de esquizofrenia

Introducción: La escala CBCL de Achenbach completada por padres evalúa un amplio rango de problemas conductuales y emocionales de inicio en la infancia. Sus subescalas “retraimiento-depresión” y principalmente “problemas de pensamiento” se han propuesto como medida de detección de riesgo de psicosis en adolescentes. Dentro de los posibles endofenotipos de la esquizofrenia se plantean la disfunción ejecutiva y la alteración en el lenguaje pragmático. Objetivos: Identificar mediante ambas subescalas de la CBCL un subgrupo de niños y adolescentes con puntuaciones elevadas entre los pacientes que consultan en psiquiatría infantil por trastornos del neurodesarrollo y que tienen antecedentes familiares de esquizofrenia. Material y métodos: Los padres completan la escala CBCL de Achenbach, CCC-Childrens Communication Checklist- (evaluación del lenguaje pragmático) y BRIEF-2 (evaluación conductual de la función ejecutiva).Resultados: Se incluyeron 21 niños (16 niños: 5 niñas). Edad media 11,4 años. Los diagnósticos principales fueron TDAH (66,7%), trastorno de aprendizaje (9,5%) y TEA (9,5%). Las dos subescalas de la CBCL “retraimiento-depresión” y “problemas de pensamiento” discriminan dos grupos, uno con afectación (n=11) con puntuaciones por encima del Pc70 y otro sin afectación (n=10) con puntuaciones inferiores al Pc70. Los casos con afectación mostraron más dificultades en el lenguaje pragmático y función ejecutiva que los del grupo sin afectación.Conclusiones: Realizar una evaluación dimensional más completa de la psicopatología, como la que ofrece la CBCL, en niños con trastornos del neurodesarrollo y antecedentes familiares de esquizofrenia puede ayudar a describir mejor las dificultades premórbidas e identificar casos susceptibles de seguimiento longitudinal e intervención precoz.

Slow wave oscillations in Schizophrenia First-Degree Relatives: A confirmatory analysis and feasibility study on slow wave traveling

Abnormal sleep oscillations have recently been proposed as endophenotypes of schizophrenia. However, optimization of methodological approaches is still necessary to standardize analyses of their microstructural characteristics. Additionally, some relevant features of these oscillations remain unexplored in pathological conditions. Among others, slow wave traveling is a promising proxy for diurnal processes of brain connectivity and excitability. The study of slow oscillations propagation appears particularly relevant when schizophrenia is conceptualized as a dys-connectivity syndrome. Given the rising knowledge on the neurobiological mechanisms underlying slow wave traveling, this measure might offer substantial advantages over other approaches in investigating brain connectivity.Herein we: 1) confirm the stability of our previous findings on slow waves and sleep spindles in FDRs using different automated algorithms, and 2) report the dynamics of slow wave traveling in FDRs of Schizophrenia patients. A 256-channel, high-density EEG system was employed to record a whole night of sleep of 16 FDRs and 16 age- and gender-matched control subjects. A recently developed, open source toolbox was used for slow wave visualization and detection. Slow waves were confirmed to be significantly smaller in FDRs compared to the control group. Additionally, several traveling parameters were analyzed. Traveled distances were found to be significantly reduced in FDRs, whereas origins showed a different topographical pattern of distribution from control subjects. In contrast, local speed did not differ between groups.Overall, these results suggest that slow wave traveling might be a viable method to study pathological conditions interfering with brain connectivity.

Hyperfunctioning of the right posterior superior temporal sulcus in response to neutral facial expressions presents an endophenotype of schizophrenia

Deficits in social cognition have been proposed as a marker of schizophrenia. Growing evidence suggests especially hyperfunctioning of the right posterior superior temporal sulcus (pSTS) in response to neutral social stimuli reflecting the neural correlates of social-cognitive impairments in schizophrenia. We characterized healthy participants according to schizotypy (n = 74) and the single-nucleotide polymorphism rs1344706 in ZNF804A (n = 73), as they represent risk variants for schizophrenia from the perspectives of personality traits and genetics, respectively. A social-cognitive fMRI task was applied to investigate the association of right pSTS hyperfunctioning in response to neutral face stimuli with schizotypy and rs1344706. Higher right pSTS activation in response to neutral facial expressions was found in individuals with increased positive (trend) and disorganization symptoms, as well as in carriers of the risk allele of rs1344706. In addition, a positive association between right–left pSTS connectivity and disorganization symptoms during neutral face processing was revealed. Although these findings warrant replication, we suggest that right pSTS hyperfunctioning in response to neutral facial expressions presents an endophenotype of schizophrenia. We assume that right pSTS hyperfunctioning is a vulnerability to perceive neutral social stimuli as emotionally or intentionally salient, probably contributing to the emergence of symptoms of schizophrenia.

The opportunity of application of neurophysiological tests — schizophrenia endophenotypes for studying the role of genetic factors in cognitive processes in healthy subjects and in psychiatric diseases

The study of effects of genetic polymorphisms implicated in dopamine (COMT, DRD2) and GABA (GAD1) activities in the prefrontal cortex on antisaccades (AS) and evoked potential P300 measures was conducted with participation of 55 healthy subjects and 72 schizophrenic patients. The significant interaction of genotype and disease was found for most of the studied AS and P300 measures. The worse task performance and decreased efficacy of cortical activation were revealed for the associated with schizophrenia risk polymorphisms.

Polymorphism in the LASP1 gene promoter region alters cognitive functions of patients with schizophrenia

Schizophrenia’s pathogenesis remains elusive. Cognitive dysfunction is the endophenotype and outcome predictor of schizophrenia. The LIM and SH3 domain protein (LASP1) protein, a component of CNS synapses and dendritic spines, has been related to the N-methyl-D-aspartate receptor (NMDAR) dysfunction hypothesis and schizophrenia. A single-nucleotide polymorphism (rs979607) in the LASP1 gene promoter region has been also implicated in schizophrenia susceptibility. The aim of this study was to investigate the role of the LASP1 rs979607 polymorphism in the cognitive functions of patients with schizophrenia. Two hundred and ninety-one Han Taiwanese patients with schizophrenia were recruited. Ten cognitive tests and two clinical rating scales were assessed. The scores of cognitive tests were standardized to T-scores. The genotyping of the LASP1 rs979607 polymorphism was performed using TaqMan assay. Among the 291 patients, 85 were C/C homozygotes of rs979607, 141 C/T heterozygotes, and 65 T/T homozygotes, which fitted the Hardy-Weinberg equilibrium. After adjusting age, gender, and education with general linear model, the C/C homozygotes performed better than C/T heterozygotes in overall composite score (p = 0.023), Category Fluency test (representing processing speed and semantic memory) (p = 0.045), and Wechsler Memory Scale (WMS)-III backward Spatial Span test (p = 0.025), albeit without correction for multiple comparisons for the latter two individual tests. To the best of our knowledge, this is the first study suggesting that the genetic variation of LASP1 may be associated with global cognitive function, category verbal fluency, and spatial working memory of patients with schizophrenia. The finding also lends support to the NMDAR dysfunction hypothesis of schizophrenia. More studies with longitudinal designs are warranted.

Social cognitive endophenotypes in schizophrenia: A study comparing first episode schizophrenia patients and, individuals at clinical- and familial- ‘at-risk’ for psychosis

Impairments in specific domains of social cognition have been suggested as possible endophenotypes for schizophrenia and clinical markers for accurate identification of ‘at-risk’ (AR) states. Aim of the present study was to find out whether performance on social cognition tasks will distinguish ‘clinical at-risk (CAR)’ and ‘familial at-risk (FAR)’ individuals from remitted first episode schizophrenia (FES) patients and healthy controls. Fifty in each of these four groups were included for analysis. Schizophrenia psychopathology in FES group was assessed using the Positive and Negative Syndrome Scale (PANSS). Theory of mind (ToM; first and second order (SOT and FOT), and faux pas composite (FPC)), attributional bias (AB) and social perception (SP) were assessed using the Social Cognition Rating Tool in Indian Setting (SOCRATIS). Facial emotion recognition task was used to assess emotional-expression recognition (ER). Significant differences in ToM, SP and ER between the four groups were found, even after controlling for performance on various neurocognitive tasks. ToM and SP were identified to follow an endophenotype pattern. While, both ToM and SP classified FES from healthy with large accuracy rates, SP, specifically, distinguished at-risk from disease groups. None of the social cognitive domains accurately classified familial at-risk from clinical at-risk groups. We conclude that social cognitive measures may be used as reliable endophenotype markers for schizophrenia and its sub-domains may be used for valid identification of AR individuals.